Progranulin-driven lysosomal acidification facilitates exocytosis of PHEV-hijacked lysosomes for viral release

Porcine hemagglutinating encephalomyelitis virus (PHEV) hijacks lysosomes, repurposing them as vehicles for viral release by disrupting their function. Progranulin (PGRN), a lysosomal glycoprotein essential for lysosomal regulation, plays a pivotal role in this process. This study demonstrates that PHEV Infection reduces full-length PGRN levels while enhancing its lysosomal targeting. Notably, PGRN knockout mice exhibit resistance to PHEV Infection, implicating PGRN in PHEV-induced lysosomal dysfunction and viral release. Mechanistically, PHEV infection-induced enhancement of PGRN lysosomal trafficking depends on the concurrent harnessing of two distinct pathways for lysosomal delivery of PGRN. This enhanced targeting involves increased vacuolar-type ATPase recruitment, intensifying lysosomal acidification and triggering Arl8b-dependent lysosomal exocytosis, facilitating viral release. Furthermore, in vivo knockdown of neuronal PGRN expression suppresses PHEV transmission within the central nervous system. These findings underscore the essential role of PGRN-mediated lysosomal acidification in driving lysosomal exocytosis, thereby contributing to PHEV release and neural dissemination during Infection. These insights provide a foundation for targeting PGRN expression and lysosomal trafficking as a potential therapeutic strategy to mitigate PHEV Infection and its neural dissemination.IMPORTANCEBetacoronaviruses exploit the lysosomal exocytic pathway for cellular egress through diverse mechanisms, often leading to lysosomal dysfunction. Porcine hemagglutinating encephalomyelitis virus (PHEV), a neurotropic porcine betacoronavirus, relies on lysosomal acidification for cell egress, in contrast to Other betacoronaviruses, such as severe acute respiratory syndrome coronavirus 2 and mouse hepatitis virus, which utilize deacidified lysosomes for release. Progranulin (PGRN), a lysosomal glycoprotein essential for regulating lysosomal function, has emerged as a critical player in this process. Here, we demonstrate that PHEV Infection enhances PGRN lysosomal trafficking, with PGRN knockout mice exhibiting resistance to PHEV Infection. Our findings reveal that PGRN expression and lysosomal targeting drive PHEV-induced lysosomal acidification, facilitating Arl8b-dependent lysosomal exocytosis and promoting viral egress. These results underscore the pivotal role of PGRN in lysosomal dysfunction and viral egress, warranting further investigation into its regulatory function during cellular egress of Other betacoronaviruses.

betacoronaviruses; central nervous system; lysosomal acidification; lysosomal exocytosis; porcine hemagglutinating encephalomyelitis virus; progranulin.